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Body weight influences SGLT2-inhibitor effects in type 1 diabetes


 

REPORTING FROM EASD 2019

In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).

“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A1c,” Dr. Danne said.

He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m2 or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.

“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.

Risk for DKA

“The big charm of these drugs is that not only do you improve A1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m2 [versus BMI of less than 27 kg/m2].”

The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.

“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.

Body weight and composition

Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.

She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.

SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.

Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).

For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.

The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.

The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.

Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.

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